Multiple lines of evidence indicate that the prefrontal cortex (PFC) may be a locus of dysfunction in schizophrenia; however, relatively little is known about the organization of the intrinsic circuitry of the expanded and highly differentiated human PFC. The first goal of this project is the characterization of the functional architecture of the primate PFC, using the macaque monkey as a model of the human. Studies 1 and 2 will examine the spatial relations and intrinsic connectivity of afferent, efferent, and intrinsic components of monkey PFC circuitry in order to test hypotheses concerning the integration of different excitatory and modulatory inputs with the intrinsic circuitry of PFC, the role of local inhibition in shaping the distribution and function of these associative interactions, and the influence of excitatory and inhibitory elements of PFC circuitry on the output of this region. Questions regarding the physiological characteristics of this circuitry will be tested in Projects 5 and 6. Given the late maturation of some functions subserved by PFC, and the tendency for schizophrenic symptoms to first appear in late adolescence, Study 3 will address specific questions about changes in neuronal morphology, connectivity and biochemistry that occur in monkey PFC in association with puberty. Findings from these studies will be used to guide the conduct and interpretation of investigations of postmortem brain specimens from schizophrenic subjects and matched controls. These investigations (Studies 4 and 5) will test specific hypotheses, derived from Project 4 and other clinical studies in our Center, about the disruption of PFC circuitry in schizophrenia.